BACKGROUND: Osteosarcoma is the most familiar primary malignant tumor occurred in bone in young people and is featured by complicated genetic changes. CD93 has been affirmed to exhibit the facilitative roles in multiple cancers. METHODS: But, the detailed impacts and related regulatory pathway of CD93 in osteosarcoma progression maintain unclear. RESULTS: In this study, the elevated expression of CD93 was verified in osteosarcoma tissues from GEO database. Additionally, it was illustrated that CD93 existed the aggrandized mRNA and protein expressions in osteosarcoma cell lines. Moreover, suppression of CD93 restrained cell proliferation and angiogenesis in osteosarcoma. It was demonstrated that inhibition of CD93 retarded immune escape in osteosarcoma. Furthermore, CD93 triggered the PI3K/AKT pathway to aggravate the progression of osteosarcoma. At last, it was discovered that knockdown of CD93 attenuated tumor growth in vivo. CONCLUSIONS: In conclusion, this study disclosed that CD93 aggravated cell proliferation, angiogenesis and immune escape in osteosarcoma through triggering the PI3K/AKT pathway. This work may supply useful opinions of CD93 on the cure of osteosarcoma.